Citalopram Versus Amitriptyline in Elderly Depressed Patients with Or

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ORIGINAL RESEARCH Key Words: depression, citalopram, amitriptyline, elderly, GP-setting

Citalopram Versus Amitriptyline in Elderly Depressed Patients with or without Mild Cognitive Dysfunction: A Danish Multicentre Trial in General Practice By Claus Rosenberg, MD, Lise Lauritzen, MD, Jørgen Brix, MD, Jørgen B. Jørgensen, MD, Palle Kofod, MD, and Liselotte Been Bayer

ABSTRACT ~ This double-blind, multicenter trial, carried out in general practice in Denmark, comprised 221 women and 70 men, aged 58–97 years, with major depression (with or without mild cognitive dysfunction) or dysthymia (DSM-III-R). Patients had a total score Ն13 on the 17-item Hamilton Depression Rating Scale (HDRS) and a score Ն20 on the Mini Mental State Examination scale. The efficacy and tolerability of citalopram (20–40 mg daily) and amitriptyline (50–100 mg daily) were compared over 12 weeks. The participating general practitioners were trained at corating sessions in the use of the HDRS and Melancholia Scale (MES) prior to and during the study. The inter-observer reliability was assessed to investigate if general practitioners were able to use scales that measure the severity of depression. The two treatments were considered equally effective; the 90% confidence interval for the difference between the treatment groups in change from baseline to end-point in HDRS total score (Ϫ0.84 to ϩ1.23) was within the predefined interval (Ϫ4 to ϩ4). Significantly more patients on citalopram (50%) than on amitriptyline (31%) reported no adverse events at all (P ϭ .001). Moreover, patients on amitriptyline reported adverse events significantly earlier and more frequently than patients on citalopram. The inter-observer reliability was highly satisfactory, with intra-class correlation coefficients (ICC-U) of .83 for the HDRS and .82 for the MES; however, the ICC-U for the Clinical Global Impressions was .54, indicating a poorer consensus in the investigators clinical judgment. Training in the use of the HDRS and MES scales improved the inter-observer reliability. Psychopharmacology Bulletin. 2007;40(1):63-73.

Claus Rosenberg, Deceased. Lise Lauritzen is affiliated with Psychiatric Hospital in Hillerød, Denmark. Jørgen Brix is a General Practitioner at Ingemanns Allé 175 A in Esbjerg, Denmark. Jørgen B. Jørgensen is a General Practitioner at Skibbrogade 16 in Tønder, Denmark. Palle Kofod is a General Practitioner at Nørretorv 1 in Vejle, Denmark. Liselotte Been Bayer is affiliated with Lundbeck Pharma A/S in Tåstrup, Denmark. To whom correspondence should be addressed: Liselotte Been Bayer, Lundbeck Pharma A/S, Dalbergstrøget 5, DK-2630 Tåstrup, Denmark; Tel: (+45) 43 71 42 70; Fax: (+45) 43 71 42 74; E-mail: [email protected]

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INTRODUCTION Depression is one of the most frequent psychiatric disorders among the elderly.1 The prevalence of depression varies in investigations, being higher in institutions for the elderly than in general practice.2,3 While the prevalence of major depression is low in the elderly,4 dysthymia and depressive symptomatology are frequent, sometimes in combination with dementia.5,6 Depressed elders have a higher mortality rate,7,8 a lower quality of life,7,9 and a higher suicide rate than healthy elders.10,11 Only limited studies exist that address the diagnosis and treatment of elderly, depressed patients. This is unfortunate, because the diagnosis and treatment of elderly depressed patients is a challenge to health pro- fessionals. With respect to diagnosis, elderly patients often present themselves with somatic symptoms, and the diagnostic rating scales most commonly used have a limited use in the elderly because of over- lap of symptoms from depression and the comorbid somatic disease(s); it is therefore difficult for the general practitioner to make a correct diagnosis of depression in the presence of comorbid somatic disease(s). 64 Consequently, elderly depressed patients often remain untreated.12 This is Rosenberg, Lauritzen, very unfortunate since these patients can be treated successfully, making Brix, et al. the correct diagnosis of depression in this setting an important issue. Treatment of the elderly is a challenge because they often receive multiple drug therapy because of concomitant diseases; drug interactions are therefore an obvious risk and the elderly are predisposed to experience adverse events (AEs) caused by these drug interactions. Since the introduction of selective serotonin reuptake inhibitors (SSRI) and antidepressants with dual action (i.e., antidepressants with an effect on both serotonin and noradrenalin), the tricyclic antidepressants (TCAs) are no longer recommended as first-choice treatment of depression in the elderly. When the TCAs are used, it is often for economic reasons and the dose is normally lower than that used in younger patients, to minimise the occurrence of AEs. For many years, the TCAs have, however, been the standard reference antidepressants in clinical trials. The present study was initiated to compare the efficacy and tolerability of citalopram and amitriptyline in elderly, depressed patients during 12 weeks of treatment. The study included investigators who were spe- cially trained in assessing efficacy utilizing the 17-item Hamilton Depression Rating Scale (HDRS)13 and the Melancholia Scale (MES).14

MATERIAL AND METHODS Men and women, aged 65 years or more, suffering from major depression or dysthymia, as defined by the DSM-III-R,15 were included. A score of Ն20 on the Mini Mental State Examination (MMSE)

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scale16 and a total score of Ն13 on the 17-item HDRS13 were also required at entry into the study.17 Patients who suffered from severe somatic disease(s), e.g., renal or hepatic insufficiency, cardiovascular disorders, prostatism, urinary retention, glaucoma, epilepsy, organic mental disease, marked mental retardation, other psychiatric disorders, alcohol or drug abuse, uncontrolled diabetes or other endocrine disease, uncontrolled hypertension, or who required treatment with guanethidine or bethanidine, were excluded. Patients who received treatment with a psychotropic medication, those with suicide risk, those with a known resistance to treatment with a SSRI or a TCA, those who had taken monoamine oxidase inhibitors (MAO-I) within the last 2 weeks, and those who had taken fluoxetine within the last 5 weeks were also excluded. All patients signed an informed consent form after the details of the study had been explained to them. The study was carried out according to the guidelines of the revised Helsinki Declaration18 and in accor- 19 dance with the guidelines for good clinical practice. Before initiation 65 of the study, it was approved by the Ethics Committee and by the Rosenberg, Lauritzen, Danish Regulatory Authorities. Brix, et al. Eligible patients entered a 12-week, double-blind treatment period and received either citalopram or amitriptyline once daily in the evening. As a titration dose during the first week, patients received 10 mg citalopram or 25 mg amitriptyline daily. In weeks 2–4, the daily dose was 20 mg citalopram or 50 mg amitriptyline. If the dose was well tolerated and the response considered satisfactory, this dose was kept unchanged for the remaining part of the study. If the response was inad- equate and the dose well tolerated, the daily dose was doubled after 4 weeks and kept fixed for the rest of the study period. Ratings for the assessment of efficacy were done at baseline and after weeks 2, 4, 6, 9, and 12. Tolerability was assessed at the same time comprising AEs and vital signs (electrocardiogram (ECG) recordings, heart rate, blood pressure, and weight). Corating sessions were conducted over a period of 2 years, prior to the initiation of the study and at regular intervals during the study. A total of 68 general practitioners in Denmark participated in these corating sessions; of these, 51 included patients. An experienced psychiatrist trained the investigators in the use of the 17-item HDRS and the MES. At these sessions, 12 video-taped interviews of depressed patients were shown, the participants rated the person taped, and their results were discussed to increase inter-observer reliability. Each investigator participated in at least six rating sessions allowing everyone to see the same tapes.

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STATISTICAL ANALYSES Efficacy analyses were based on data from all randomized patients who 1) fulfilled all inclusion criteria, 2) remained in the study for at least 4 weeks, 3) had at least one valid post-baseline assessment, and 4) did not receive prohibited medication. The prospectively defined primary efficacy analysis was an analysis of covariance (with baseline HDRS total score as the covariate) of the difference between the two treatment groups in change of HDRS total score from baseline to last valid HDRS assessment. The two treatments were predefined as being equivalent if the 90% confidence interval for the mean difference was completely within the interval from Ϫ4 to ϩ4 (a clinically relevant difference20). The intra-class correlation coefficient (ICC-U)21 was used as a measure of the inter-observer reliability. Spearman correlation coefficients described the convergent validity of the scales, and the Cronbach’s alpha the homogeneity.22 Safety analyses were based on data from patients who were random- 66 ized and had received at least one dose of medication. Treatment- Rosenberg, Lauritzen, emergent adverse events (TEAEs) were defined as events recorded Brix, et al. during treatment, which were either not present at baseline or wors- ened during treatment compared to baseline. TEAEs were tabulated and analysed using Fisher’s exact test.

RESULTS

Patient Disposition and Demographics A total of 291 patients entered the study (155 in the citalopram group and 136 in the amitriptyline group). There were 221 women and 70 men with a mean age of 75.7 Ϯ 6.8 years (range, 58–97 years; one patient was Ͻ65 years). Of the 291 patients, 66 were excluded from the efficacy evaluation for the following reasons: treatment for less than 4 weeks or no HDRS assessment after 4 weeks or later (50 patients), lack of compliance (9 patients), or failure to fulfil the entry criteria (7 patients). Thus, 225 patients were eligible for efficacy analysis (118 treated with citalopram and 107 treated with amitriptyline). The demographic data for the 225 patients are shown in Table 1. The majority of the patients in both groups (98%) suffered from major depression with or without dysthymia. There were no statistically significant differences between the two treatment groups. A total of 213 patients completed the 12-week study (117 (75.5%) patients in the citalopram group and 96 (70.6%) in the amitriptyline

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TABLE 1

DEMOGRAPHIC DATA

CITALOPRAM AMITRIPTYLINE (n ϭ 118)a (n ϭ 107)a Men 34 (29%) 20 (19%) Women 84 (71%) 87 (81%) Mean age Ϯ SD 75.2 Ϯ 6.1 75.3 Ϯ 7.2 Range 65–92 58b–97 With dementiac 14 (12%) 17 (16%) Without dementia 104 (88%) 90 (84%) Major depression 67 (57%) 58 (54%) Dysthymia 2 (2%) 2 (2%) Major depression ϩ dysthymia 49 (42%) 47 (44%)

aA total of 66 patients were excluded from the efficacy evaluation. bOne patient was Ͻ65 years. cDementia defined as MMSE Յ23.

Rosenberg C, Lauritzen L, Brix J, et al. Psychopharmacology Bulletin. Vol. 40. No. 1. 2007.

group). Thus, 38 patients (25%) in the citalopram group and 40 patients 67 (29%) in the amitriptyline group withdrew prematurely from the study Rosenberg, Lauritzen, for the following reasons: AEs (citalopram 14%, amitriptyline 13%); Brix, et al. lack of efficacy (both groups 1%); other reasons (citalopram 10%, amitriptyline 15%). The daily treatment dose was doubled after 4 weeks for 26 of the 118 patients (22%) treated with citalopram and for 12 of the 107 patients (11%) treated with amitriptyline. For approximately half of the patients in both groups, the increased dose resulted in an improved response to treatment.

Efficacy The mean total HDRS scores are shown in Figure 1. The difference between the two groups in changes of the mean total HDRS score from baseline to each assessment point was within the interval Ϫ0.5 to ϩ0.5, and at end-point the 90% confidence interval (Ϫ0.84 to ϩ1.23) was within the predefined interval from Ϫ4 to ϩ4. This means that the two treatments were considered to be equivalent in efficacy. The analysis of the Intention-to-treat population (all randomized patients who received at least one dose of medication) confirmed this result (the 90% confidence interval was from Ϫ0.25 to ϩ1.92). The equivalent efficacy of the two treatments was seen in both demented and non-demented patients.

Inter-observer Reliability A high degree of inter-observer reliability in the rating of depression was demonstrated (Table 2).

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FIGURE 1

TIME COURSE FOR MEAN TOTAL HDRS SCORE IN EACH TREATMENT GROUP (n ϭ 225), PATIENTS WITH OR WITHOUT DEMENTIA (MMSE Յ 23; LOCF,LAST OBSERVATION CARRIED FORWARD)

68 Rosenberg, Lauritzen, Brix, et al.

Rosenberg C, Lauritzen L, Brix J, et al. Psychopharmacology Bulletin. Vol. 40. No. 1. 2007.

TABLE 2

INTER-OBSERVER RELIABILITY

INTER-OBSERVER RELIABILITY (ICC-U) CRONBACH’S ALPHA MES 0.82 0.87 HDRS-17 0.83 0.88 HDRS-17 (sub-scale)a 0.76 0.84 CGI 0.54 0.67

N ϭ 428. aHDRS-17 melancholia sub-scale.

Rosenberg C, Lauritzen L, Brix J, et al. Psychopharmacology Bulletin. Vol. 40. No. 1. 2007.

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Tolerability Of the 291 patients included in the study, 9 patients were excluded from the safety evaluation due to lack of compliance (4 of them did not receive study medication). Thus, the tolerability analyses were based on 282 patients (151 treated with citalopram and 131 treated with amitriptyline). Significantly more patients on citalopram (50%) than on amitriptyline (31%) reported no AEs (P ϭ .001). The number of AEs per patient decreased during the treatment period and was consistently lower in the citalopram group than in the amitriptyline group, except at baseline (Table 3). The frequency of TEAEs per group, recorded in at least 5% of the patients in one of the two groups, is presented in Table 4. In both groups, two events exceeded a frequency of 10%. Dry mouth was the most frequently

TABLE 3

PRESENCE OF ADVERSE EVENTS OVER TIME 69 Rosenberg, Lauritzen, BASELINE WEEKS 1–4 WEEKS 5–8 WEEKS 9–12 Brix, et al. Citalopram Amitriptyline Citalopram Amitriptyline Citalopram Amitriptyline Citalopram Amitriptyline (n ϭ 151)a (n ϭ 131)a (n ϭ 135) (n ϭ 115) (n ϭ 122) (n ϭ 110) (n ϭ 117) (n ϭ 96) No. of AEs 40 23 138 136 82 100 62 84 Mean no. 0.26 0.18 1.02 1.18 0.67 0.91 0.53 0.88 of AEs per patient

aA total of 9 patients were excluded from the safety evaluation.

Rosenberg C, Lauritzen L, Brix J, et al. Psychopharmacology Bulletin. Vol. 40. No. 1. 2007.

TABLE 4

TEAES OCCURRING IN AT LEAST 5% OF THE PATIENTS IN ONE OF THE TWO TREATMENT GROUPS

CITALOPRAM (n ϭ 151)a AMITRIPTYLINE (n ϭ 131)a ADVERSE EVENT n (%) n (%) Nausea 19 (12.6%)* 4 (3.1%) Dry mouth 19 (12.6%) 59 (45.0%)** Dizziness 12 (7.9%) 13 (9.9%) Headache 10 (6.6%) 4 (3.1%) Fatigue 10 (6.6%) 5 (3.8%) Diarrhea 10 (6.6%)*** 2 (1.5%) Constipation 5 (3.3%) 16 (12.2%)****

aA total of 66 patients were excluded from the efficacy evaluation. *P ϭ .002; **P Ͻ .0001; ***P ϭ .02; ****P ϭ .005.

Rosenberg C, Lauritzen L, Brix J, et al. Psychopharmacology Bulletin. Vol. 40. No. 1. 2007.

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recorded event (45.0% of patients in the amitriptyline group and 12.6% of the patients in the citalopram group, P Ͻ.0001). Constipation was significantly more frequent in the amitriptyline group (P ϭ .005), whereas nausea (P ϭ .002) and diarrhoea (P ϭ .02) were significantly more frequent in the citalopram group. There was no statistically significant difference between the groups for the remaining TEAEs. There were no clinically significant changes from baseline in vital signs or ECG recordings in any of the treatment groups. A total of 31 serious adverse events (SAEs) were recorded, 18 in the citalopram group and 13 in the amitriptyline group. In the citalopram group, one case of somnolence and one case of vertigo were considered related to treatment, whereas one case of cardiac failure in the amitriptyline group was considered related to treatment. For all the other SAEs, a causal relationship between the test treatment and the event was considered unlikely by the investigator.

DISCUSSION 70 This study compared citalopram and amitriptyline in the treatment of Rosenberg, Lauritzen, depressed elderly patients in general practice in Denmark for a period Brix, et al. of 12 weeks, which is considered to be an adequate duration for a short- term trial.23 The lack of clinical study data in very old patients has frequently been pointed out as a significant problem.24 The present study included patients who were above 80 and 90 years old and the mean age was 75 years, which is satisfactory for an elderly study. It thus provides study data in a highly relevant age group. The aim of the study was to compare the efficacy and tolerability of an SSRI and a TCA. Citalopram and amitriptyline were chosen, because the general practitioners used these two drugs in their daily practice. Citalopram and amitriptyline were equally effective in treating depression in the elderly, with a better AE profile for citalopram. The daily dose was 20–40 mg of citalopram and 50–100 mg of amitriptyline, which for both drugs is in agreement with the recommendations in The Danish Drug Catalogue25,26 and, additionally, for citalopram by Montgomery and Johnson.27 For the majority of the patients in both groups, the daily dose was not increased. For citalopram, a daily dose of 20 mg to elderly patients treated in general practice is common. A daily dose of 50 mg amitriptyline might appear rather low, even in elderly patients treated in general practice; nevertheless, about three-quarters of the patients improved globally much or very much, indicating that the daily dose was sufficient for these patients. A similar trial was carried out in the United Kingdom, comprising a total of 365 elderly, depressed patients.26 As in the present study, Kyle et al (1998) demonstrated equal efficacy of the two drugs. With respect to the tolerability of the two drugs, the study by Kyle et al26 showed that

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there was a significantly higher frequency of dry mouth and of somnolence in the amitriptyline group and a significantly higher frequency of nausea in the citalopram group. In addition, fatigue and constipation were twice as frequent in the amitriptyline group as in the citalopram group, but the difference did not reach a 5% statistical significance level. In the present study, dry mouth and constipation were significantly more frequent in the amitriptyline group than in the citalopram group, whereas nausea and diarrhoea were significantly more frequent in the citalopram group than in the amitriptyline group. Thus, the results of the present study confirm the results published by Kyle et al.26 The results in the present study also confirm the results published by Dencker and Høpfner Petersen28 and by Baldwin and Johnson.29 Furthermore, the study confirms the results of a large trial, comprising 472 depressed patients, which was carried out in general practice.30 This study showed that citalopram, in the dose ranges of 20–30 mg and 40–60 mg daily, was equally effective as imipramine in the dose range of 100–150 mg daily, but that several AEs were significantly more frequent in the imipramine group than in the citalopram group. 71 To be effective, antidepressants need to be taken in sufficient doses for Rosenberg, Lauritzen, an adequate period of time. This poses a special obstacle in elderly peo- Brix, et al. ple who are at risk of AEs, because they may have age-related changes in metabolism and concomitant diseases resulting in multiple drug therapy. This study showed that citalopram was equally effective as the TCA amitriptyline, but with a better AE profile. Most AEs caused by the drug are mainly present during the initiation of the treatment. The inter-observer reliability in the rating of depression was highly satisfactory in this study, ensuring that reliable data were obtained. It indi- cates that the investigators benefited from the corating sessions and training in the use of the HDRS and MES scales. In contrast, the ICC-U for the Clinical Global Impression was low, indicating a poorer consensus among the investigators in their clinical judgement of the patients. This may reflect the investigators different views of the concept of depression and underlines the necessity of training and arranging corating sessions when performing controlled clinical studies. Citalopram’s selective mode of action, low potential for drug–drug interactions,31 and good tolerability (presumably resulting in increased compliance) supports its use for the elderly, depressed patients,32 also for long-term preventive treatment.33

CONCLUSION It is concluded that • Citalopram and amitriptyline were equivalent regarding efficacy in elderly, depressed patients treated in general practice.

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• Patients treated with amitriptyline reported AEs significantly earlier and more frequently during treatment than patients treated with citalopram. • Significantly more patients on citalopram (50%) than on amitriptyline (31%) did not report AEs. • There was a high degree of inter-observer reliability in the rating of depression. ✤

ACKNOWLEDGMENT The authors thank the following general practitioners for their par- ticipation in the study: Henrik Alsbæk, Hillerød; Hans Jørgen Andersen, Århus C; Poul Andreassen, Århus N; Jørgen Aude, Århus C; Ole Bech, Haslev; Ole Bjarne Hansen, Herning; Hans Christian Risborg, Århus C; Klaus Darling, Skive; Hans E. Simonsen, Hørning; Poul Erik Heldgaard, Tjele; Sven Erling Mehlsen, Auning; Ib Fræmohs, Allingåbro; Hans Fuglsang-Damgaard, Havndal; Carl Fynboe, Ålborg; Mogens Gliese, Glostrup; Allan Gravesen, Korsør; 72 Svend Hede, Ålborg; Jørgen Bach Holm, Århus N; Merete Holm, Rosenberg, Lauritzen, København Ø; Henrik Høncke, Århus C; Nis Jepsen, Tønder; Bjarne Brix, et al. Jensen, Ørsted; Christen Juhl, Esbjerg; Thorkild Knudsen, Nørager; Kjeld Kristensen, Tårs; Niels L. Frandsen, Esbjerg; Villy Lade, Hjørring; Henning Laursen, Skanderborg; Torben Lemminger, Øster- Vraa; Jan Meyer-Christensen, Hobro; Jørgen Munck, Ørsted; Jens- Axel Mysager, Ålborg; Henry Mølhede Christensen, Randers; Jørgen Nielsen, Nykøbing F; Søren Okholm, Århus C; Erik Otte, Stenstrup; Niels Peter Sejr, Åbyhøj; Kasper Reuther, Bagsværd; Gerhard Seth Sørensen, Nørager; Jørgen Solgaard, Tønder; Per Toft-Christensen, Vejle; Bjarne Uhrenholt, Ålborg; Steen Vejlø, Vejle; Preben Vind, Gedser; Ebbe Wendel Eriksen, Vejle; Tage Yde, Nørre-Snede; Peter Aaquist, Nørager. We also acknowledge Bente Krag Ingvardsen for her assistance in preparing the manuscript.

DECLARATION OF INTEREST Study sponsorship by H. Lundbeck A/S

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